title: Growth factor receptor-bound protein 2 promotes autophagic removal of amyloid-β protein precursor intracellular domain overload in neuronal cells.
abstract: The ascertainment of elevated levels of amyloid-β protein precursor intracellular domain (AICD) in Alzheimer's disease (AD) brains and the fact that it contributes to AD-like pathology has geared the search toward a new paradigm. While studying endogenous as well as overexpressed Grb2-AICD interaction in AD cell models, it was found that Grb2 co-localized to compartments along with AICD. We report now that these vesicles form in a clathrin and dynamin independent manner. Both types of vesicles mature into autophagosomes, merge with lysosomes, and relieve the cells of AICD overload. Inhibiting autophagosome formation results in vesicle accumulation. AICD-level is reduced in Grb2 excess condition in Cycloheximide Chase setup. Reduced caspase activity and apoptosis point toward the fact that the cytotoxic effect of AICD is alleviated by its sequestration in autolysosomes. Hence we state that the entrapping of AICD in Grb2 vesicles and its clearance via autophagosomes is a survival contrivance on the part of the cell. This study unravels, for the first time, the roles of Grb2 in autophagy and in handling toxic protein overload in an AD-like scenario.
authors.affiliation: Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, WB, Kolkata, India.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Roy
authors.forename: Mithu
authors.initials: M
authors.lastname: Raychaudhuri
authors.forename: Oishee
authors.initials: O
authors.lastname: Chakrabarti
authors.forename: Debashis
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D051380:GRB2 Adaptor Protein / Q000502:physiology* / Q000633:toxicity; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology
chemical_list: D016564:Amyloid beta-Protein Precursor; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human
keywords: Amyloid-β protein precursor protein; CD63; Grb2; LC3 protein; autophagy; clathrin; dynamin